Tuberculosis (TB) is the leading opportunistic cause of death among AIDS patients and is responsible for the loss of almost 3 million lives each year. Studies from our laboratories have associated a specific family of HLA alleles (HLA-DQ beta57-Asp) with elevated risk for progression to active pulmonary disease among a group of Cambodian rural poor suffering from one of the highest global incidences of TB. We have also uncovered a high incidence of antigen-specific anergy to PPD (purified protein derivative) among patients with active pulmonary disease that persists following successful cure. This persistent anergy may be associated with the same HLA type. The proposed studies will expand our initial assessment of HLA alleles with disease and anergy, attempt to establish the clinical relevance of anergy and HLA type in TB, explore the molecular mechanisms involved in anergy at the transcriptional level, and explore the role of antigen-specific anergy and different immunomodulatory TB strains in HIV-1 regulation. In Specific Aim 1 we propose to (1) solidify the correlation of HLA-DQ ?57-Asp with anergy and susceptibility to TB by HLA-typing additional anergic patients in Cambodia, (2) compare the HLA type of HIV/AIDS patients suffering from TB with the HLA type of those that avoid TB infection to uncover more subtle effects in this highly vulnerable population, (3) determine the functional consequences of anergy by looking at the rate of bacterial clearance in anergic TB patients undergoing antituberculosis chemotherapy, (4) determine the functional consequences of anergy by HLA typing patients that experience a poor clinical outcome and relapse with active disease following apparently successful chemotherapy and (5) determine whether HLA-DQ ?57-Asp effects the presentation of Mtb-derived antigens. In Specific Aim 2 we propose to (1) study the molecular mechanism of anergy in the infected host by exploring the nature of chromatin structure and remodeling in T-cells from PPD-anergic patients, and (2) determine the role of specific transcription factors in anergy. In Specific Aim 3 we will examine the impact of PPD-driven T cell activation in the setting of HIV-1 infection and we will determine whether monocyte tropic as well as T cell tropic primary HIV-1 isolates are regulated differently in PPD-responsive versus PPD-anergic cells. Furthermore, we will clarify the role of different immunomodulatory MTb strains in the regulation of T and M tropic HIV-1 primary isolates+ Finally, MTb strains from anergic and PPD-responsive patients will be isolated and molecularly characterized and will be tested for distinct effects upon T and M tropic primary HIV-1 isolates. Taken together, these experiments should allow us to elucidate basic mechanisms in MTb and HIV-1 coinfection and suggest novel immunomodulatory therapeutic strategies to decrease both viral load and MTb burden. Furthermore, these experiments will yield important basic insights into TB susceptibility and the molecular mechanisms of antigen-specific anergy. They may also contribute to our ability to predict treatment failure, prioritize patients for chemoprophylaxis, and design effective peptide vaccines.